Preparation method of selective estrogen receptor alpha covalent antagonist

Abstract

The invention relates to a preparation method of a selective estrogen receptor alpha covalent antagonist. The invention particularly relates to a preparation method of a compound E-7. The method is simple to operate and suitable for industrial production. # imgabs0 #

Description

Technical Field

[0001] The present disclosure belongs to the field of medicine and relates to a preparation method of a selective estrogen receptor α covalent antagonist. Background Art

[0002] Breast cancer is one of the most common malignant tumors in women.

[0003] Approximately 70% of breast cancer patients have estrogen receptor (ER)-positive breast cancer. In the treatment of this part of breast cancer patients, endocrine therapy plays an important role. Although endocrine therapy is the preferred treatment for estrogen receptor-positive breast cancer, about 30% of the patients receiving adjuvant therapy will relapse, and almost all metastatic breast cancer patients will develop drug resistance and progress.

[0004] ESR1 gene mutation may be one of the mechanisms of drug resistance in estrogen-positive breast cancer. In subsequent studies, a certain proportion of ESR1 gene mutations were found in estrogen receptor-positive metastatic breast cancer patients, and the mutation rate was approximately around 30%. Therefore, it is necessary to develop estrogen receptor antagonists targeting ESR1 gene mutations.

[0005] WO2020253762A1 provides a selective estrogen receptor α covalent antagonist, the structure of which is shown below. This compound has a significant inhibitory effect on estrogen receptor reporter genes.

[0006]

[0007] WO2020253762A1 also discloses a preparation method of the aforementioned compound. For the consideration of simplifying the preparation process, controlling the product quality, and meeting the requirements of industrial production, the present disclosure provides a new preparation method of this compound and its pharmaceutically acceptable salts. Summary of the Invention

[0008] The present disclosure provides a preparation method of a compound represented by formula V-3 or its pharmaceutically acceptable salt, including the step of reacting a compound represented by formula V-2 with a compound represented by formula I-5 under the action of a palladium catalyst.

[0009]

[0010] Wherein,

[0011] R 1 is selected from C 1-6 alkyl, and the C 1-6 alkyl is optionally substituted by one or more halogens;

[0012] R 2Selected from H or F;

[0013] R 3 Same or different, each independently selected from H, halogen or C 1-6 alkyl;

[0014] m is an integer selected from 0 - 5 (e.g., 0, 1, 2, 3, 4, 5);

[0015] R 11 、R 12 Same or different, each independently selected from H or C 1-6 alkyl, or R 11 and R 12 forms a C 3-8 cycloalkyl with the carbon atom to which it is attached;

[0016] R 13 、R 14 Same or different, each independently selected from H or C 1-6 alkyl, or R 13 and R 14 forms a C 3-8 cycloalkyl with the carbon atom to which it is attached;

[0017] X is selected from Ts or Tf;

[0018] Y is selected from -B(OR)2,

[0019] PG is an amino protecting group;

[0020] R is selected from H or C 1-6 alkyl.

[0021] In some embodiments, X is Ts and Y is

[0022] In some embodiments, PG is THP.

[0023] In some embodiments, m is an integer selected from 0 - 2 (e.g., 0, 1, 2).

[0024] In some embodiments, the palladium catalyst is selected from PdCl2(Xantphos), Pd(OAc)2 or PdCl2(dppf).

[0025] In some specific embodiments, the palladium catalyst is PdCl2(Xantphos).

[0026] In some embodiments, for the preparation method of the compound of formula V - 3 or its pharmaceutically acceptable salt, the method comprises the step of reacting compound E - 2 with compound A - 5 to obtain compound E - 3,

[0027]

[0028] On the other hand, the present disclosure provides a method for preparing a compound of formula V-2 or a pharmaceutically acceptable salt thereof, which includes the step of reacting a compound of formula V-1 with an acid anhydride X2O,

[0029]

[0030] wherein R 1 、R 3 、R 11 、R 12 、R 13 、R 14 、m and X are respectively as defined in the compound of formula V-2.

[0031] In some embodiments, the method for preparing a compound of formula V-2 or a pharmaceutically acceptable salt thereof includes the step of reacting compound E-1 with p-toluenesulfonic anhydride to obtain compound E-2,

[0032]

[0033] In some embodiments, the method for preparing a compound of formula V-3 or a pharmaceutically acceptable salt thereof provided by the present disclosure further includes the steps in the method for preparing a compound of formula V-2 or a pharmaceutically acceptable salt thereof described above.

[0034] On the other hand, the present disclosure provides a method for preparing a compound of formula V-1 or a pharmaceutically acceptable salt thereof, which includes the step of reacting a compound of formula Ⅲ-4 with a compound of formula Ⅱ-3,

[0035]

[0036] wherein X 1 is selected from F or Cl;

[0037] R 1 、R 3 、R 11 、R 12 、R 13 、R 14 、m are respectively as defined in the compound of formula V-2.

[0038] In some embodiments, X 1 is Cl.

[0039] In some embodiments, the method for preparing a compound of formula V-1 or a pharmaceutically acceptable salt thereof includes the step of reacting compound C-4 with compound B-3 to obtain compound E-1,

[0040]

[0041] In some embodiments, the method for preparing the compound represented by formula V-3 or a pharmaceutically acceptable salt thereof provided by the present disclosure further includes the steps in the method for preparing the compound represented by formula V-2 or a pharmaceutically acceptable salt thereof described above, and optionally includes the steps in the method for preparing the compound represented by formula V-1 or a pharmaceutically acceptable salt thereof described above.

[0042] In some embodiments, the method for preparing the compound represented by formula V-3 or a pharmaceutically acceptable salt thereof provided by the present disclosure further includes the steps in the method for preparing the compound represented by formula V-2 or a pharmaceutically acceptable salt thereof described above.

[0043] In an alternative embodiment, the method for preparing the compound represented by formula V-3 or a pharmaceutically acceptable salt thereof provided by the present disclosure includes the steps in the method for preparing the compound represented by formula V-1 or a pharmaceutically acceptable salt thereof described above.

[0044] On the other hand, the present disclosure provides a method for preparing a compound represented by formula V-4 or a pharmaceutically acceptable salt thereof, including the step of removing Phth from the compound represented by formula V-3,

[0045]

[0046] wherein R 1 , R 2 , R 3 , R 11 , R 12 , R 13 , R 14 , m, and PG are respectively as defined in the compound represented by formula V-3.

[0047] In some embodiments, the method for preparing the compound represented by formula V-4 or a pharmaceutically acceptable salt thereof includes the step of removing Phth from the compound represented by formula V-3 to obtain the hydrochloride salt of the compound represented by formula V-4,

[0048]

[0049] wherein R 1 , R 2 , R 3 , R 11 , R 12 , R 13 , R 14 , m, and PG are respectively as defined in the compound represented by formula V-3.

[0050] In some embodiments, the method for preparing the compound represented by formula V-4 or a pharmaceutically acceptable salt thereof includes the step of removing Phth from compound E-3 to obtain compound E-4.

[0051]

[0052] In some embodiments, the method for preparing the compound of formula V-4 or a pharmaceutically acceptable salt thereof includes the step of removing Phth from compound E-3 to obtain the hydrochloride salt of compound E-4.

[0053]

[0054] In some embodiments, the method for preparing the compound of formula V-4 or a pharmaceutically acceptable salt thereof provided by the present disclosure further includes the steps in the method for preparing the compound of formula V-3 or a pharmaceutically acceptable salt thereof as described above, optionally including the steps in the method for preparing the compound of formula V-2 or a pharmaceutically acceptable salt thereof as described above, and optionally including the steps in the method for preparing the compound of formula V-1 or a pharmaceutically acceptable salt thereof as described above.

[0055] In some embodiments, the method for preparing the compound of formula V-4 or a pharmaceutically acceptable salt thereof provided by the present disclosure further includes the steps in the method for preparing the compound of formula V-3 or a pharmaceutically acceptable salt thereof as described above.

[0056] In an alternative embodiment, the method for preparing the compound of formula V-4 or a pharmaceutically acceptable salt thereof provided by the present disclosure includes the steps in the method for preparing the compound of formula V-2 or a pharmaceutically acceptable salt thereof as described above.

[0057] In an alternative embodiment, the method for preparing the compound of formula V-4 or a pharmaceutically acceptable salt thereof provided by the present disclosure includes the steps in the method for preparing the compound of formula V-1 or a pharmaceutically acceptable salt thereof as described above.

[0058] On the other hand, the present disclosure provides a method for preparing a compound of formula V-5 or a pharmaceutically acceptable salt thereof, which includes the step of reacting the compound of formula V-4 with the compound of formula VI.

[0059]

[0060] wherein, R 4 is selected from H, C 1-6 alkoxy, halogen, C 1-6 alkyl;

[0061] n is an integer from 0 to 5 (for example, 0, 1, 2, 3, 4, 5);

[0062] R 1 , R 2 , R 3 , R 11 , R 12 , R 13 , R 14 , m, and PG are respectively defined as in the compound of formula V-3.

[0063] In some embodiments, n is selected from integers from 0 to 2 (e.g., 0, 1, 2).

[0064] In some embodiments, R4 is methoxy.

[0065] In some embodiments, a method for preparing a compound of formula V-5 or a pharmaceutically acceptable salt thereof comprises reacting the hydrochloride salt of the compound of formula V-4 with a compound of formula VI to obtain the hydrochloride salt of the compound of formula V-5.

[0066]

[0067] wherein, R 4 is selected from H, C 1-6 alkoxy, halogen, C 1-6 alkyl;

[0068] n is selected from integers from 0 to 5 (e.g., 0, 1, 2, 3, 4, 5);

[0069] R 1 、R 2 、R 3 、R 11 、R 12 、R 13 、R 14 、m, and PG are as defined in the compound of formula V-3, respectively.

[0070] In some embodiments, n is selected from integers from 0 to 2 (e.g., 0, 1, 2).

[0071] In some embodiments, R4 is methoxy.

[0072] In some embodiments, the method for preparing the compound of formula V-5 or a pharmaceutically acceptable salt thereof comprises reacting compound E-4 with 2,4-dimethoxybenzaldehyde to obtain compound E-5.

[0073]

[0074] In some embodiments, the method for preparing the compound of formula V-5 or a pharmaceutically acceptable salt thereof comprises reacting the hydrochloride salt of compound E-4 with 2,4-dimethoxybenzaldehyde to obtain the hydrochloride salt of compound E-5.

[0075]

[0076] In some embodiments, the method for preparing the compound represented by formula V-5 or a pharmaceutically acceptable salt thereof provided by the present disclosure further includes the steps in the method for preparing the compound represented by formula V-4 or a pharmaceutically acceptable salt thereof as described above, optionally includes the steps in the method for preparing the compound represented by formula V-3 or a pharmaceutically acceptable salt thereof as described above, optionally includes the steps in the method for preparing the compound represented by formula V-2 or a pharmaceutically acceptable salt thereof as described above, and optionally includes the steps in the method for preparing the compound represented by formula V-1 or a pharmaceutically acceptable salt thereof as described above.

[0077] In some embodiments, the method for preparing the compound represented by formula V-5 or a pharmaceutically acceptable salt thereof provided by the present disclosure further includes the steps in the method for preparing the compound represented by formula V-4 or a pharmaceutically acceptable salt thereof as described above.

[0078] In an alternative embodiment, the method for preparing the compound represented by formula V-5 or a pharmaceutically acceptable salt thereof provided by the present disclosure includes the steps in the method for preparing the compound represented by formula V-3 or a pharmaceutically acceptable salt thereof as described above.

[0079] In an alternative embodiment, the method for preparing the compound represented by formula V-5 or a pharmaceutically acceptable salt thereof provided by the present disclosure includes the steps in the method for preparing the compound represented by formula V-2 or a pharmaceutically acceptable salt thereof as described above.

[0080] In an alternative embodiment, the method for preparing the compound represented by formula V-5 or a pharmaceutically acceptable salt thereof provided by the present disclosure includes the steps in the method for preparing the compound represented by formula V-1 or a pharmaceutically acceptable salt thereof as described above.

[0081] On the other hand, the present disclosure provides a method for preparing a compound represented by formula V-6 or a pharmaceutically acceptable salt thereof, including the step of reacting the compound represented by formula V-5 with the compound represented by formula VII,

[0082]

[0083] wherein, R 5 and R 6 are the same or different and are each independently selected from H, C 1-6 alkyl, or R 5 and R 6 form a 4- to 6-membered heterocycle with the nitrogen atom to which they are attached, wherein the 4- to 6-membered heterocycle optionally contains an oxygen atom;

[0084] R 1 、R 2 、R 3 、R 11 、R 12 、R 13 、R 14 、m, and PG are as defined in the compound represented by formula V-3;

[0085] L is as in the compound R1 -L is defined in;

[0086] R 4 and n are respectively defined as in the compound of formula V-5.

[0087] In some embodiments, the method for preparing the compound of formula V-6 or a pharmaceutically acceptable salt thereof comprises the step of reacting the hydrochloride salt of the compound of formula V-5 with the compound of formula VII,

[0088]

[0089] wherein R 5 and R 6 are the same or different and are each independently selected from H, C 1-6 alkyl, or R 5 and R 6 together with the nitrogen atom to which they are attached form a 4-6 membered heterocycle, wherein the 4-6 membered heterocycle optionally contains an oxygen atom;

[0090] R 1 、R 2 、R 3 、R 11 、R 12 、R 13 、R 14 、m, PG are respectively defined as in the compound of formula V-3;

[0091] L is defined as in the compound R 1 -L;

[0092] R 4 、n are respectively defined as in the compound of formula V-5.

[0093] In some embodiments, the method for preparing the compound of formula V-6 or a pharmaceutically acceptable salt thereof comprises the step of reacting compound E-5 with compound F to obtain compound E-6,

[0094]

[0095] In some embodiments, the method for preparing the compound of formula V-6 or a pharmaceutically acceptable salt thereof comprises the step of reacting the hydrochloride salt of compound E-5 with compound F to obtain compound E-6,

[0096]

[0097] In some embodiments, the method for preparing the compound of formula V-6 or a pharmaceutically acceptable salt thereof provided by the present disclosure further includes the steps in the method for preparing the compound of formula V-5 or a pharmaceutically acceptable salt thereof described above, optionally includes the steps in the method for preparing the compound of formula V-4 or a pharmaceutically acceptable salt thereof described above, optionally includes the steps in the method for preparing the compound of formula V-3 or a pharmaceutically acceptable salt thereof described above, optionally includes the steps in the method for preparing the compound of formula V-2 or a pharmaceutically acceptable salt thereof described above, and optionally includes the steps in the method for preparing the compound of formula V-1 or a pharmaceutically acceptable salt thereof described above.

[0098] In some embodiments, the method for preparing the compound of formula V-6 or a pharmaceutically acceptable salt thereof provided by the present disclosure further includes the steps in the method for preparing the compound of formula V-5 or a pharmaceutically acceptable salt thereof described above.

[0099] In an alternative embodiment, the method for preparing the compound of formula V-6 or a pharmaceutically acceptable salt thereof provided by the present disclosure includes the steps in the method for preparing the compound of formula V-4 or a pharmaceutically acceptable salt thereof described above.

[0100] In an alternative embodiment, the method for preparing the compound of formula V-6 or a pharmaceutically acceptable salt thereof provided by the present disclosure includes the steps in the method for preparing the compound of formula V-3 or a pharmaceutically acceptable salt thereof described above.

[0101] In an alternative embodiment, the method for preparing the compound of formula V-6 or a pharmaceutically acceptable salt thereof provided by the present disclosure includes the steps in the method for preparing the compound of formula V-2 or a pharmaceutically acceptable salt thereof described above.

[0102] In an alternative embodiment, the method for preparing the compound of formula V-6 or a pharmaceutically acceptable salt thereof provided by the present disclosure includes the steps in the method for preparing the compound of formula V-1 or a pharmaceutically acceptable salt thereof described above.

[0103] On the other hand, the present disclosure provides a method for preparing a compound of formula V-7 or a pharmaceutically acceptable salt thereof, including the steps of removing PG from the compound of formula V-6 and the step of

[0104]

[0105] wherein R 1 、R 2 、R 3 、R 11 、R 12 、R 13 、R 14 、m, and PG are respectively as defined in the compound of formula V-3;

[0106] R 4 and n are respectively as defined in the compound of formula V-5;

[0107] R 5 、R 6 are defined as in the compounds of formula V-6, respectively.

[0108] In some embodiments, the method for preparing the compound of formula V-7 or a pharmaceutically acceptable salt thereof includes the step of removing THP and DMB from compound E-6 to obtain compound E-7.

[0109]

[0110] In some embodiments, the method for preparing the compound of formula V-7 or a pharmaceutically acceptable salt thereof provided by the present disclosure further includes the steps in the method for preparing the compound of formula V-6 or a pharmaceutically acceptable salt thereof, optionally includes the steps in the method for preparing the compound of formula V-5 or a pharmaceutically acceptable salt thereof, optionally includes the steps in the method for preparing the compound of formula V-4 or a pharmaceutically acceptable salt thereof, optionally includes the steps in the method for preparing the compound of formula V-3 or a pharmaceutically acceptable salt thereof, optionally includes the steps in the method for preparing the compound of formula V-2 or a pharmaceutically acceptable salt thereof, and optionally includes the steps in the method for preparing the compound of formula V-1 or a pharmaceutically acceptable salt thereof.

[0111] In some embodiments, the method for preparing the compound of formula V-7 or a pharmaceutically acceptable salt thereof provided by the present disclosure further includes the steps in the method for preparing the compound of formula V-6 or a pharmaceutically acceptable salt thereof.

[0112] In an alternative embodiment, the method for preparing the compound of formula V-7 or a pharmaceutically acceptable salt thereof provided by the present disclosure includes the steps in the method for preparing the compound of formula V-5 or a pharmaceutically acceptable salt thereof.

[0113] In an alternative embodiment, the method for preparing the compound of formula V-7 or a pharmaceutically acceptable salt thereof provided by the present disclosure includes the steps in the method for preparing the compound of formula V-4 or a pharmaceutically acceptable salt thereof.

[0114] In an alternative embodiment, the method for preparing the compound of formula V-7 or a pharmaceutically acceptable salt thereof provided by the present disclosure includes the steps in the method for preparing the compound of formula V-3 or a pharmaceutically acceptable salt thereof.

[0115] In an alternative embodiment, the method for preparing the compound of formula V-7 or a pharmaceutically acceptable salt thereof provided by the present disclosure includes the steps in the method for preparing the compound of formula V-2 or a pharmaceutically acceptable salt thereof.

[0116] In alternative embodiments, the method for preparing the compound represented by Formula V-7 or a pharmaceutically acceptable salt thereof provided by the present disclosure includes the steps in the method for preparing the compound represented by Formula V-1 or a pharmaceutically acceptable salt thereof described above.

[0117] On the other hand, the present disclosure provides a method for preparing a compound represented by Formula III-4 or a pharmaceutically acceptable salt thereof, including the following steps,

[0118]

[0119] wherein, L is selected from halogen;

[0120] R 1 、R 3 、m are respectively defined as in the compound represented by Formula V-2;

[0121] X 1 is defined as in the compound represented by Formula III-4.

[0122] In some embodiments, the compound III-1 or a pharmaceutically acceptable salt thereof reacts with N,O-dimethylhydroxylamine or its hydrochloride to obtain the compound III-2 or a pharmaceutically acceptable salt thereof.

[0123] In some embodiments, the compound III-2 or a pharmaceutically acceptable salt thereof reacts with to obtain the compound III-3 or a pharmaceutically acceptable salt thereof, wherein, R 3 、m are respectively defined as in the compound represented by Formula V-2, and X 1 is defined as in the compound represented by Formula III-4.

[0124] In some embodiments, the compound III-3 reacts with R 1 -L to obtain the compound III-4;

[0125] wherein, L is selected from halogen;

[0126] R 1 、R 3 、m are respectively defined as in the compound represented by Formula V-2;

[0127] X 1 is defined as in the compound represented by Formula III-4.

[0128] In some specific embodiments, the compound III-1 reacts with N,O-dimethylhydroxylamine or its hydrochloride to obtain the compound III-2, the compound III-2 reacts with to obtain the compound III-3, and the compound III-3 reacts with R 1 -L to obtain the compound III-4;

[0129] wherein, L is selected from halogen;

[0130] R 1 、R3 , m are as defined in the compound of formula V-2;

[0131] X 1 as defined in the compound of formula III-4.

[0132] In some embodiments, the method for preparing the compound of formula III-4 or a pharmaceutically acceptable salt thereof comprises the following steps,

[0133]

[0134] In some embodiments, compound C-1 is reacted with N,O-dimethylhydroxylamine or its hydrochloride to obtain compound C-2.

[0135] In some embodiments, compound C-2 is reacted with PhCH2MgBr to obtain compound C-3.

[0136] In some embodiments, compound C-3 is reacted with to obtain compound C-4.

[0137] In some specific embodiments, compound C-1 is reacted with N,O-dimethylhydroxylamine or its hydrochloride to obtain compound C-2, compound C-2 is reacted with PhCH2MgBr to obtain compound C-3, and compound C-3 is reacted with to obtain compound C-4.

[0138] On the other hand, the present disclosure provides a method for preparing a compound B-3 or a pharmaceutically acceptable salt thereof, comprising the following steps,

[0139]

[0140] In some embodiments, compound B-1 is reacted with N-ethoxycarbonylphthalimide to obtain compound B-2.

[0141] In some embodiments, compound B-2 is reduced with BH3·Me2S to obtain compound B-3.

[0142] In some specific embodiments, compound B-1 is reacted with N-ethoxycarbonylphthalimide to obtain compound B-2, and compound B-2 is reduced with BH3·Me2S to obtain compound B-3.

[0143] On the other hand, the present disclosure provides a method for preparing a compound A-5 or a pharmaceutically acceptable salt thereof, comprising the following steps,

[0144]

[0145] In some embodiments, compound A-1 is reacted with 3,4-dihydro-2H-pyran to obtain compound A-2.

[0146] In some embodiments, compound A-2 reacts with the selective fluorinating reagent Selectfluor to give compound A-3.

[0147] In some embodiments, compound A-3 reacts with 3,4-dihydro-2H-pyran to give compound A-4.

[0148] In some embodiments, compound A-4 reacts with bis(pinacolato)diboron in the presence of a palladium catalyst to give compound A-5.

[0149] In some specific embodiments, compound A-1 reacts with 3,4-dihydro-2H-pyran to give compound A-2, compound A-2 reacts with the selective fluorinating reagent Selectfluor to give compound A-3, compound A-3 reacts with 3,4-dihydro-2H-pyran to give compound A-4, and compound A-4 reacts with bis(pinacolato)diboron in the presence of a palladium catalyst to give compound A-5.

[0150] In some embodiments, the palladium catalyst is PdCl2(dppf).

[0151] The present disclosure provides a compound of formula III-4' or a pharmaceutically acceptable salt thereof,

[0152]

[0153] wherein R 1 is selected from C 1-6 alkyl, and the C 1-6 alkyl is substituted with one or more halogens;

[0154] R 3 , m, X 1 are as described above, respectively.

[0155] In some embodiments, the compound of formula III-4 provided by the present disclosure or a pharmaceutically acceptable salt thereof is compound C-4

[0156] The present disclosure provides a compound of formula V-1 or a pharmaceutically acceptable salt thereof,

[0157]

[0158] wherein R 1 , R 3 , R 11 , R 12 , R 13 , R 14 and m are as described above, respectively.

[0159] In some embodiments, the present disclosure provides a compound of formula V-1 or a pharmaceutically acceptable salt thereof, which is compound E-1

[0160] The present disclosure provides a compound of formula V-2 or a pharmaceutically acceptable salt thereof,

[0161]

[0162] wherein R 1 、R 3 、R 11 、R 12 、R 13 、R 14 、m, and X are as described above.

[0163] In some embodiments, the present disclosure provides a compound of formula V-2 or a pharmaceutically acceptable salt thereof, which is compound E-2

[0164] The present disclosure provides a compound of formula V-3 or a pharmaceutically acceptable salt thereof,

[0165]

[0166] wherein R 1 、R 2 、R 3 、R 11 、R 12 、R 13 、R 14 、m, and PG are as described above.

[0167] In some embodiments, the present disclosure provides a compound of formula V-3 or a pharmaceutically acceptable salt thereof, which is compound E-3

[0168] The present disclosure provides a compound of formula V-5 or a pharmaceutically acceptable salt thereof,

[0169]

[0170] wherein R 1 、R 2 、R 3 、R 4 、R 11 、R 12 、R 13 、R 14 、m, n, and PG are as described above.

[0171] In some embodiments, the present disclosure provides a compound of formula V-5 or a pharmaceutically acceptable salt thereof, which is compound E-5,

[0172] The present disclosure provides a compound of formula V-6 or a pharmaceutically acceptable salt thereof,

[0173]

[0174] wherein R 1 、R 2 、R 3 、R 4 、R 5 、R 6 、R 11 、R 12 、R 13 、R 14 、m, n, and PG are as described above.

[0175] In some embodiments, the compound of formula V-6 or a pharmaceutically acceptable salt thereof provided by the present disclosure is compound E-6

[0176] Glossary of Terms

[0177] For easier understanding of the present disclosure, certain technologies and sciences are specifically defined below. Unless otherwise clearly defined in the present disclosure, all other technologies and sciences used in the present disclosure have the meanings commonly understood by those of ordinary skill in the art to which the present disclosure pertains.

[0178] The term "alkyl" refers to a saturated aliphatic hydrocarbon group, including straight-chain and branched-chain groups having 1 to 20 carbon atoms. Alkyl groups having 1 to 6 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, and various branched isomers thereof, etc. The alkyl group can be substituted or unsubstituted. When substituted, the substituent can be substituted at any available attachment point, preferably one or more of the following groups, independently selected from halogen, deuterium, hydroxyl, oxo, nitro, cyano, C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyloxy, C 2-6 alkynyloxy, C 3-6 cycloalkoxy, 3- to 6-membered heterocycloalkoxy, C 3-8 cycloalkenyloxy, 5- to 6-membered aryl or heteroaryl, wherein the C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyloxy, C 2-6 alkynyloxy, C 3-6 cycloalkoxy, 3- to 6-membered heterocycloalkoxy, C 3-8The cycloalkenyloxy group, 5- to 6-membered aryl or heteroaryl group is optionally substituted with one or more substituents selected from halogen, deuterium, hydroxyl, oxo, nitro, and cyano.

[0179] The term "alkoxy" refers to -O-(alkyl), where alkyl is as defined above. Non-limiting examples of alkoxy groups include: methoxy, ethoxy, propoxy, butoxy. The alkoxy group can be optionally substituted or unsubstituted. When substituted, the substituents are preferably one or more of the following groups, independently selected from halogen, hydroxyl, oxo, cyano, amino, C 1-6 alkyl, C 1-6 alkoxy, 3- to 7-membered cycloalkyl or 3- to 7-membered heterocycloalkyl, where the alkyl, alkoxy, cycloalkyl or heterocycloalkyl is optionally substituted with halogen, hydroxyl, nitro, cyano or amino

[0180] The term "cycloalkyl" or "carbocyclic ring" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, where the cycloalkyl ring contains 3 to 20 carbon atoms, preferably 3 to 8 carbon atoms. Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, etc.; polycyclic cycloalkyl groups include spiro, fused and bridged cycloalkyls. The cycloalkyl group can be substituted or unsubstituted. When substituted, the substituents can be substituted at any available attachment point, preferably one or more of the following groups, independently selected from halogen, deuterium, hydroxyl, oxo, nitro, cyano, C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyloxy, C 2-6 alkynyloxy, C 3-6 cycloalkoxy, 3- to 6-membered heterocycloalkoxy, C 3-8 cycloalkenyloxy, 5- to 6-membered aryl or heteroaryl, where the C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyloxy, C 2-6 alkynyloxy, C 3-6 cycloalkoxy, 3- to 6-membered heterocycloalkoxy, C 3-8 cycloalkenyloxy group, 5- to 6-membered aryl or heteroaryl group is optionally substituted with one or more substituents selected from halogen, deuterium, hydroxyl, oxo, nitro, and cyano.

[0181] The cycloalkyl ring can be fused to an aryl or heteroaryl ring, where the ring attached to the parent structure is cycloalkyl. Non-limiting examples include indanyl, tetrahydronaphthyl, benzocycloheptyl, etc. The cycloalkyl group can be optionally substituted or unsubstituted. When substituted, the substituents are preferably one or more of the following groups, independently selected from halogen, deuterium, hydroxyl, oxo, nitro, cyano, C 1-6 alkyl, C 1-6 alkoxy, C 2-6Alkenyloxy, C 2-6 Alkynyloxy, C 3-6 Cycloalkyloxy, 3- to 6-membered hetero cycloalkyloxy, C 3-8 Cycloalkenyloxy, 5- to 6-membered aryl or heteroaryl, said C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyloxy, C 2-6 Alkynyloxy, C 3-6 Cycloalkyloxy, 3- to 6-membered hetero cycloalkyloxy, C 3-8 Cycloalkenyloxy, 5- to 6-membered aryl or heteroaryl optionally substituted with one or more substituents selected from halogen, deuterium, hydroxy, oxo, nitro, cyano.

[0182] The term "heterocycloalkyl" or "heterocycle" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent containing 3 to 20 ring atoms, wherein one or more ring atoms are heteroatoms selected from nitrogen, oxygen or S(O) m (where m is an integer from 0 to 2), but excluding the ring moieties of -O-O-, -O-S- or -S-S-, and the remaining ring atoms are carbon. Preferably contains 3 to 12 ring atoms, of which 1 to 4 are heteroatoms; more preferably contains 3 to 7 ring atoms. Even more preferably contains 4 to 6 ring atoms. Non-limiting examples of monocyclic heterocycloalkyl include pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, etc. Polycyclic heterocycloalkyl includes spiro, fused and bridged heterocycloalkyl. Non-limiting examples of "heterocycloalkyl" include:

[0183]

[0184] And so on.

[0185] The heterocycloalkyl ring can be fused to an aryl or heteroaryl ring, where the ring connected to the parent structure is heterocycloalkyl, and non-limiting examples thereof include:

[0186] And so on.

[0187] Heterocycloalkyl can be optionally substituted or unsubstituted. When substituted, the substituents are preferably one or more of the following groups, which are independently selected from halogen, deuterium, hydroxy, oxo, nitro, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyloxy, C 2-6 Alkynyloxy, C 3-6 Cycloalkyloxy, 3- to 6-membered hetero cycloalkyloxy, C 3-8 Cycloalkenyloxy, 5- to 6-membered aryl or heteroaryl, said C1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyloxy, C 2-6 alkynyloxy, C 3-6 cycloalkoxy, 3- to 6-membered heterocycloalkoxy, C 3-8 cycloalkenyloxy, 5- to 6-membered aryl or heteroaryl optionally substituted with one or more substituents selected from halogen, deuterium, hydroxyl, oxo, nitro, cyano.

[0188] The "amino protecting group" of the present disclosure is a group known in the art that can be used to protect an amino group, see the amino protecting groups in the literature ("Protective Groups in Organic Synthesis", 5 Th Ed. T. W. Greene & P. G. M. Wuts). By way of example, and without limitation, include carbamate protecting groups such as 2-trimethyl-silylethoxycarbonyl (Teoc), 1-methyl-1-(4-biphenylyl)-ethoxy-carbonyl (Bpoc), tert-butoxycarbonyl (BOC), allyloxycarbonyl (Alloc), 9-fluorenylmethyloxycarbonyl (Fmoc), and benzyloxycarbonyl (Cbz); amide protecting groups such as formyl, acetyl, trichloroacetyl, benzoyl, and nitrophenylacetyl; sulfonamide-protecting groups such as 2-nitrobenzenesulfonyl; and imine and cyclic imine protecting groups such as phthalimido and dithiosuccinyl.

[0189] In the chemical structure of the compounds described in the present disclosure, the bond " / " represents an unspecified configuration, that is, if there are chiral isomers in the chemical structure, the bond " / " can be or simultaneously contain both configurations.

[0190] The pharmaceutically acceptable salts of the compounds described in the present disclosure are selected from inorganic salts or organic salts.

[0191] The compounds of the present disclosure can exist in specific geometric or stereoisomeric forms. The present disclosure contemplates all such compounds, including cis- and trans-isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereoisomers, (D)-isomers, (L)-isomers, and their racemic mixtures and other mixtures, such as enantiomer- or diastereomer-enriched mixtures, all of which mixtures are within the scope of the present disclosure. Additional asymmetric carbon atoms may be present in substituents such as alkyl. All such isomers and their mixtures are included within the scope of the present disclosure.

[0192] In addition, the compounds and intermediates of the present disclosure may also exist in different tautomeric forms, and all such forms are included within the scope of the present disclosure. The term "tautomer" or "tautomeric form" refers to structural isomers of different energies that can interconvert via a low energy barrier. For example, prototropic tautomers (also known as proton-transfer tautomers) include interconversions via proton migration, such as keto-enol and imine-enamine, lactam-lactim isomerization. An example of the lactam-lactim equilibrium is between A and B shown below.

[0193]

[0194] All compounds in the present invention can be drawn in the form of A or B. All tautomeric forms are within the scope of the present invention. The naming of the compounds does not exclude any tautomers.

[0195] "Optional" or "optionally" means that the subsequently described event or circumstance may, but need not, occur, and this description includes the cases where the event or circumstance occurs or does not occur. For example, "optionally halogen- or cyano-substituted C1-6 alkyl" means that halogen or cyano may, but need not, be present, and this description includes the cases where the alkyl is substituted by halogen or cyano and the cases where the alkyl is not substituted by halogen and cyano.

[0196] Unless the context clearly requires otherwise, throughout the specification and claims, the words "comprise", "have", "include", etc. shall be construed in an inclusive sense, rather than an exclusive or exhaustive sense; that is, the sense of "including but not limited to". Detailed Description

[0197] The following examples are used to further describe the present disclosure, but these examples do not limit the scope of the present disclosure.

[0198] For the experimental methods without specific conditions in the examples or test examples of the present disclosure, they are generally carried out under conventional conditions, or according to the conditions recommended by the raw material or commodity manufacturer. Reagents without specific sources indicated are conventional reagents purchased from the market.

[0199] Abbreviation List

[0200] EDCI: 1-Ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride

[0201] HOBt: 1-Hydroxybenzotriazole

[0202] Ts: p-Toluenesulfonyl

[0203] Tf: Trifluoromethanesulfonyl

[0204] Phth: Phthaloyl

[0205] DMB: 2,4 - Dimethoxybenzyl

[0206] DCM: Dichloromethane

[0207] THF: Tetrahydrofuran

[0208] DMF: N,N - Dimethylformamide

[0209] PTSA: p - Toluenesulfonic acid

[0210] DHP: 3,4 - Dihydro - 2H - pyran

[0211] THP: Tetrahydropyranyl

[0212] Selectfluor: 1 - Chloromethyl - 4 - fluoro - 1,4 - diazabicyclo[2.2.2]octane bis(tetrafluoroborate)

[0213] PdCl2(dppf): Dichlorobis(1,1'-bis(diphenylphosphino)ferrocene)palladium(II)

[0214] PdCl2(Xantphos): Dichloro(4,5 - bis(diphenylphosphino)-9,9 - dimethylxanthene)palladium(II)

[0215] The structure of the compound was determined by nuclear magnetic resonance (NMR). The NMR shift (δ) is given in units of 10 -6 (ppm). The NMR measurements were performed on a Bruker AVANCE - 400 NMR spectrometer, and the solvents used were deuterated dimethyl sulfoxide (DMSO - d6), deuterated chloroform (CDCl3), deuterated methanol (CD3OD), and the internal standard was tetramethylsilane (TMS).

[0216] The HPLC measurements were carried out using a Shimadzu LC - 20A systems, Shimadzu LC - 2010HT series or Agilent 1200LC high - performance liquid chromatograph (Ultimate XB - C18 3.0*150mm column or Xtimate C18 2.1*30mm column).

[0217] The thin - layer chromatography silica gel plates used were Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plates. The specifications of the silica gel plates used for thin - layer chromatography (TLC) were 0.15 mm - 0.2 mm, and the specifications for separating and purifying products by thin - layer chromatography were 0.4 mm - 0.5 mm.

[0218] Column chromatography generally used silica gel with a mesh size of 100 - 200, 200 - 300, or 300 - 400 from Yantai Huanghai as the carrier.

[0219] The known starting materials of the present disclosure can be used or synthesized according to methods known in the art, or can be purchased from companies such as ABCR GmbH&Co.KG, Acros Organics, Aldrich Chemical Company, AccelaChemBio Inc, Darui Chemicals, etc.

[0220] Unless otherwise specified in the examples, the reactions can all be carried out under an argon or nitrogen atmosphere.

[0221] The argon or nitrogen atmosphere means that the reaction flask is connected to an argon or nitrogen balloon with a volume of about 1 L.

[0222] Unless otherwise specified in the examples, the solution refers to an aqueous solution.

[0223] Unless otherwise specified in the examples, the reaction temperature is room temperature, which is 20°C to 30°C.

[0224] The progress of the reactions in the examples was monitored by thin-layer chromatography (TLC). For the developing agent used in the reaction, the eluent system of column chromatography for purifying the compound, and the developing agent system of thin-layer chromatography, the volume ratio of the solvents was adjusted according to the polarity of the compound, and a small amount of basic or acidic reagents such as triethylamine and acetic acid could also be added for adjustment.

[0225] Example 1

[0226] 3-Fluoro-1-(tetrahydro-2H-pyran-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole

[0227]

[0228] Synthesis of Intermediate A-5

[0229]

[0230] Step 1:

[0231] 94 g of Compound A-1 was weighed into a reaction kettle, then 900 mL of acetonitrile was added, the air was evacuated and replaced with argon, and then 9 g of p-toluenesulfonic acid monohydrate was added. The temperature of the reaction system was cooled to below 10°C, and 80 g of 3,4-dihydro-2H-pyran was added dropwise. After the addition was completed in 0.5 h, the temperature was raised to room temperature and stirred until the raw materials were completely converted. Water and ethyl acetate were added to the reaction solution for extraction. The organic phases were combined, washed with saturated sodium carbonate solution and saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain crude product A-2 (180 g), which was directly used in the next step.

[0232] Step 2:

[0233] Dissolve 12.3 g of A-2 in 120 mL of acetonitrile, then add 31 g of the selective fluorinating reagent Selectfluor and 5.3 g of acetic acid. Heat the mixture from room temperature to 70 °C. After detecting that the reaction is complete, cool it down to room temperature, filter, wash the residue with ethyl acetate, collect the filtrate and rotary evaporate until no liquid drips. The residue is extracted with ethyl acetate and water, the organic phase is washed with saturated brine and dried over anhydrous sodium sulfate. Collect the filtrate, perform column chromatography with silica sand to obtain the target compound A-3 (6.2 g, yield: 66%).

[0234] 1 H NMR (400 MHz, d6-DMSO) δ 9.95 (s, 1H), 7.86 (s, 1H), 7.54 (d, 1H, J = 8.4 Hz), 7.33 (d, 1H, J = 8.4 Hz).

[0235] Step 3:

[0236] Add 8.6 g of compound A-3, 0.8 g of p-toluenesulfonic acid monohydrate and 50 mL of DCM to the reaction flask. Replace the gas with nitrogen three times, cool it down to 0 - 10 °C, dropwise add 4.4 g of compound 3,4-dihydro-2H-pyran. After dropping, let it warm up to room temperature naturally. When the system is basically clear, and TLC shows that the raw materials are completely converted, wash it successively with saturated sodium bicarbonate and saturated brine, rotary evaporate the organic phase to dryness, and perform column chromatography to obtain the product A-4 (10.3 g, yield: 86%).

[0237] 1 H NMR (400 MHz, d6-DMSO) δ 7.79 (d, 1H, J = 1.6 Hz), 7.49 (dd, 1H, J = 1.6, 8.8 Hz), 7.40 (dd, 1H, J = 1.6, 8.8 Hz), 5.56 (dt, 1H, J = 2.4, 9.2 Hz), 4.00 - 3.96 (m, 1H), 3.75 - 3.70 (m, 1H), 2.46 - 2.38 (m, 1H), 2.14 - 1.99 (m, 2H), 1.78 - 1.61 (m, 3H).

[0238] Step 4:

[0239] Add 39 g of compound A-4, 38.5 g of compound KOAc, 39.9 g of compound bis(pinacolato)diboron, 957 mg of compound PdCl2(dppf) and 200 mL of toluene to the reaction flask. Replace the gas with argon, stir and heat up to 90 °C, keep the temperature until the raw materials are completely converted. After cooling to room temperature, add water and ethyl acetate for extraction. The organic phase is washed with saturated brine and dried over anhydrous sodium sulfate. Filter, distill the organic phase under reduced pressure to dryness, and perform column chromatography to obtain compound A-5 (37.1 g, 82%).

[0240] 1 1H NMR (400 MHz, d6-DMSO) δ 8.19 (s, 1H), 7.83 (d, 1H, J = 8.4 Hz), 7.47 (dd, 1H, J = 1.2, 8.8 Hz), 5.59 (dt, 1H, J = 2.4, 8.8 Hz), 4.03 - 3.99 (m, 1H), 3.75 - 3.68 (m, 1H), 2.51 - 2.42 (m, 1H), 2.16 - 2.11 (m, 1H), 2.05 - 1.99 (m, 1H), 1.79 - 1.59 (m, 3H), 1.37 (s, 12H).

[0241] Example 2

[0242] 2-(1-(Hydroxymethyl)cyclopropyl)isoindoline-1,3-dione

[0243]

[0244] Synthesis of Compound B-3

[0245]

[0246] Step 1:

[0247] Weigh 5.24 g of sodium carbonate into the reaction flask, add 50 mL of deionized water, stir until clear, add 5 g of Compound B-1 at room temperature, stir evenly, and then add 22.8 g of N-ethoxycarbonylphthalimide to the reaction solution in portions. Stir overnight at room temperature. After the reaction is complete, cool the reaction system in an ice bath and adjust the reaction pH to 1 - 2 with 6M hydrochloric acid aqueous solution. Filter, wash with deionized water until the filtrate is neutral, and dry to obtain Compound B-2 (10.31 g, yield: 89.3%).

[0248] 1 1H NMR (400 MHz, d6-DMSO) δ 13.06 (s, 1H), 7.91 - 7.86 (m, 4H), 1.67 - 1.64 (m, 2H), 1.48 - 1.44 (m, 2H).

[0249] Step 2:

[0250] 80 g of compound B-2 was weighed into a reaction flask, 800 mL of dry THF was added, and the gas was replaced with argon. The internal temperature of the reaction system was maintained at 10 °C, and 260 mL of borane dimethyl sulfide (2 M) was slowly added dropwise into the reaction system at 10 °C, keeping the internal temperature below 15 °C. After the addition was complete, the temperature was raised to 37 °C and the reaction was carried out overnight. After the reaction was completed, the internal temperature of the reaction system was lowered to 0 °C, and methanol was slowly added to quench the reaction, keeping the internal temperature not exceeding 10 °C. After the addition was complete, the temperature was raised to room temperature and stirred for a period of time. The reaction system was distilled under reduced pressure, and the residue was slurried with an ethanol aqueous solution for 2 hours. After filtration and drying, compound B-3 (52.1 g, yield: 65.1%) was obtained.

[0251] 1 H NMR (400 MHz, CDCl3) δ 7.84 - 7.82 (m, 2H), 7.73 - 7.71 (m, 2H), 3.69 (s, 2H), 2.12 (s, 1H), 7.14 - 7.12 (m, 4H).

[0252] Example 3

[0253] 1-(6-Chloropyridin-3-yl)-4,4,4-trifluoro-2-phenylbutan-1-one

[0254]

[0255] Synthesis of Intermediate C-4

[0256]

[0257] Step 1:

[0258] 500 g of compound C-1, 7.5 L of acetonitrile, 371.5 g of dimethylhydroxylamine hydrochloride, 730 g of EDCI, and 42.9 g of HOBt were added to a 20 L reaction kettle. The gas was replaced with nitrogen, and the mixture was stirred to form a brown clear solution. 385.4 g of triethylamine was added dropwise at room temperature, and the reaction was carried out at room temperature until the reaction of C-1 was complete as monitored by TLC. The insoluble salts were filtered off, the filter cake was washed with ethyl acetate, the filtrate was concentrated to dryness, then water and ethyl acetate were added for extraction. The organic phase was washed once with water, saturated Na2CO3, and saturated NaCl respectively. After drying, the organic phase was rotary evaporated to obtain product C-2 (480.0 g, yield: 76%).

[0259] 1 H NMR (400 MHz, CDCl3) δ 8.77 (d, 1H, J = 2.0 Hz), 8.02 (dd, 1H, J = 2.4, 8.4 Hz), 7.39 (dd, 1H, J = 0.4, 8.4 Hz), 3.56 (s, 3H), 3.39 (s, 3H).

[0260] Step 2:

[0261] 10.3 g of compound C-2 and 30 mL of dry THF were added to a reaction flask. After purging with nitrogen, the temperature was lowered to about -5 °C in an ice-salt bath. 57 mL of benzylmagnesium bromide (1 M) was slowly added dropwise while controlling the temperature not to exceed 5 °C. After the reaction was completed, the organic phase was added dropwise to saturated ammonium chloride to quench the reaction. After liquid separation, the organic phase was further extracted with saturated brine and separated. The organic phase was distilled under reduced pressure to dryness, and then slurried with n-heptane. The product C-3 (11.3 g, yield 81%) was obtained by filtration.

[0262] 1 H NMR (400 MHz, CDCl3) δ 8.98 (d, 1H, J = 2.0 Hz), 8.20 (dd, 1H, J = 2.4, 8.4 Hz), 7.41 (dd, 1H, J = 0.4, 8.4 Hz), 7.36 - 7.23 (m, 5H), 4.26 (s, 2H).

[0263] Step 3:

[0264] 8.2 g of compound C-3 was weighed into a reaction flask, and 80 mL of DMF was added. Then 6.9 mL of trifluoroiodoethane was added, and the temperature was lowered in an ice-water bath for 10 minutes. KOH was added in one portion, and then the temperature was slowly raised. Stirring was carried out under the condition that the internal temperature was maintained at 11 - 15 °C. It could be observed that the reaction system turned reddish-brown. After the reaction was completely converted, saturated ammonium chloride solution was added to quench the reaction. It was extracted with methyl tert-butyl ether, and compound C-4 (8 g, yield: 73%) was obtained after column chromatography.

[0265] 1 H NMR (400 MHz, CDCl3) δ 8.95 (d, 1H, J = 2.0 Hz), 8.18 (dd, 1H, J = 2.4, 8.4 Hz), 7.40 - 7.28 (m, 6H), 4.80 (dd, 1H, J = 5.6, 7.2 Hz), 3.38 - 3.26 (m, 1H), 2.63 - 2.50 (m, 1H).

[0266] Example 4

[0267] (E)-1-Morpholino-4-((1-(((5-((Z)-4,4,4-Trifluoro-1-(3-fluoro-1H-indazol-5-yl)-2-phenylbut-1-en-1-yl)pyridin-2-yl)oxy)methyl)cyclopropyl)amino)but-2-en-1-one

[0268]

[0269] Synthesis of Compound E-7

[0270]

[0271] Step 1:

[0272] Weigh 20 g of compound C-4 and 15.9 g of compound B-3 into a 500 mL three-necked flask, add 160 mL of toluene, place it in an oil bath and preheat to an internal temperature of 65 °C. Add 11.4 g of potassium tert-butoxide all at once. After addition, raise the temperature to 90 °C and keep it warm for half an hour. Monitor the reaction by TLC until it is complete. Quench the reaction by adding semi-saturated brine and cool the reaction system to room temperature. Collect the organic phase, extract the aqueous phase once with methyl tert-butyl ether, combine the organic phases, and dry over anhydrous sodium sulfate. Distill off the organic solvent under reduced pressure, add ethanol to azeotrope to remove the solvent, then add ethanol, stir to dissolve and crystallize. Filter, wash the filter cake with ethanol, and dry in vacuo to obtain compound E-1 (31.52 g, yield: 85.8%).

[0273] 1 H NMR (400 MHz, d6-DMSO) δ 8.61 (d, 1H, J = 2.4 Hz), 8.19 (dd, 1H, J = 8.8, 2.4 Hz), 7.80 - 7.74 (m, 4H), 7.35 - 7.21 (m, 5H), 6.75 (d, 1H, J = 8.8 Hz), 5.03 (t, 1H, J = 6.92 Hz), 4.52 (q, 2H, J = 12.0 Hz), 3.25 - 3.12 (m, 1H), 2.76 - 2.62 (m, 1H), 1.20 - 1.12 (m, 4H).

[0274] Step 2:

[0275] Weigh 5 g of compound E-1 into a reaction flask, add 30 mL of anhydrous THF, displace the gas with argon, and cool to an internal temperature of -10 °C. Add 1.4 g of solid sodium tert-butoxide to the reaction system all at once, and stir at an internal temperature of -10 °C for half an hour. Then slowly add dropwise a THF solution (50 mL) containing 4.6 g of p-toluenesulfonic anhydride to the reaction system, keeping the internal temperature not exceeding 0 °C. Continue stirring until the raw materials are completely converted. Quench the reaction by adding saturated brine at low temperature, separate the organic phase, and extract the aqueous phase once with methyl tert-butyl ether. Combine the organic phases, dry over anhydrous sodium sulfate, and concentrate under reduced pressure to remove the solvent. Add ethanol for pulping, then add deionized water for pulping overnight. Filter, wash the filter cake with ethanol, and dry in vacuo to obtain compound E-2 (5 g, yield: 76.2%).

[0276] 11H NMR (400 MHz, d6-DMSO) δ 7.83 (s, 4H), 7.46 (d, 2H, J = 8.4 Hz), 7.33 (d, 1H, J = 2.0 Hz), 7.27 (d, 2H, J = 8.4 Hz), 7.22 - 7.21 (m, 3H), 7.09 - 7.03 (m, 3H), 6.31 (d, 1H, J = 8.4 Hz), 4.29 (s, 2H), 3.65 (q, 2H, J = 10.8 Hz), 2.29 (s, 3H), 1.12 (s, 4H).

[0277] Step 3:

[0278] Weigh 7.7 g of compound E-2, 4.5 g of compound A-5 and 39 mL of toluene into a reaction flask, add an aqueous potassium phosphate solution (4 g dissolved in 12 mL), add 90 mg of compound PdCl2(XantPhos), displace the gas with argon, heat from room temperature to 90 °C and keep the reaction at this temperature. TLC shows that the reaction is complete. Cool down to room temperature, extract and separate with EA. Combine the organic phases, spin-dry, add ethanol and stir at room temperature, filter, wash the filter cake with ethanol, and dry under vacuum to obtain compound E-3 (6.8 g, yield: 81.6%).

[0279] 1 1H NMR (400 MHz, d6-DMSO) δ 7.82 (dd, 1H, J = 8.8, 1.2 Hz), 7.70 (s, 4H), 7.51 (s, 1H), 7.21 - 7.10 (m, 8H), 6.41 (d, 1H, J = 8.8 Hz), 5.85 (d, 1H, J = 9.6 Hz), 4.32 (q, 2H, J = 12.0 Hz), 3.90 (d, 1H, J = 12.0 Hz), 3.89 (d, 1H, J = 11.6 Hz), 3.48 - 3.35 (m, 2H), 2.35 - 2.23 (m, 1H), 2.08 - 1.95 (m, 2H), 1.80 - 1.70 (m, 1H), 1.60 - 1.58 (m, 2H), 1.10 - 1.05 (m, 4H).

[0280] Step 4:

[0281] Weigh 11.5 g of compound E-3 into a reaction flask, add 115 mL of ethanol, stir at room temperature, add 20.5 g of aqueous methylamine solution (25 wt%), then gradually heat the reaction system to 50 °C and stir overnight. TLC shows that the raw materials are completely converted. The reaction solution is concentrated under reduced pressure until most of the ethanol is removed. The residue is dissolved and layered with dichloromethane and water. Combine the organic phases, wash them with water and aqueous sodium chloride solution respectively. Add anhydrous sodium sulfate to the organic phase for drying. Filter, concentrate under reduced pressure to remove most of the dichloromethane, add acetone for azeotropic distillation, then add acetone to dissolve. Cool the filtrate to 10 - 15 °C, slowly add 1.4 mL of concentrated hydrochloric acid dropwise. After the addition is complete, heat to room temperature and keep warm for crystallization overnight. Filter, filter with suction until no liquid drips, wash the filter cake with acetone, and dry it under vacuum to obtain the hydrochloride of compound E-4 (8.4 g, yield: 89.6%).

[0282] 1 H NMR (400 MHz, d6-DMSO) δ 8.63 (s, 3H), 7.84 (d, 1H, J = 8.8 Hz), 7.66 (s, 2H), 7.36 (dd, 1H, J = 8.8, 1.6 Hz), 7.30 - 7.18 (m, 6H), 6.62 (d, 1H, J = 8.8 Hz), 5.83 (d, 1H, J = 9.6 Hz), 4.21 (s, 2H), 3.89 (d, 1H, J = 11.6 Hz), 3.75 - 3.71 (m, 1H), 3.47 (q, 2H, J = 10.8 Hz), 2.31 - 2.22 (m, 1H), 2.05 - 1.95 (m, 2H), 1.80 - 1.70 (m, 1H), 1.60 - 1.58 (m, 2H), 1.04 (t, 2H, J = 6.4 Hz), 0.85 (t, 2H, J = 6.4 Hz).

[0283] Step 5:

[0284] 8.3 g of the hydrochloride salt of compound E-4 and 2.25 g of 2,4-dimethoxybenzaldehyde were weighed into a reaction flask, 80 mL of dichloromethane was added, and the mixture was stirred at room temperature. Triethylamine was added dropwise at room temperature, and the addition was completed in about 0.5 h. The system gradually became clear and was kept at room temperature (25 - 30 °C) overnight for 18 h. Subsequently, the reaction system was cooled to 15 - 20 °C, and sodium triacetoxyborohydride was added in 3 batches. After the addition, the temperature was returned to room temperature and stirred for 3 h. Sampling for TLC showed that the raw materials were completely converted. The system was cooled to 0 - 10 °C, and 41.5 mL of sodium hydroxide aqueous solution (1 N) was slowly added dropwise. After the addition, the temperature was returned to room temperature and stirred for another 0.5 h. The mixture was allowed to stand for liquid separation. The aqueous phase was extracted again with dichloromethane. The combined organic phases were washed with sodium chloride aqueous solution (20%). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure until no liquid dropped. Methyl tert-butyl ether was added to dissolve it, and 1.2 mL of dioxane hydrochloride was added dropwise at room temperature. After the addition, it was stirred overnight at room temperature, filtered, and the filter cake was rinsed with methyl tert-butyl ether and dried in vacuo to obtain the hydrochloride salt of compound E-5 (10.3 g, yield: 99%).

[0285] 1 H NMR (400 MHz, d6-DMSO) δ 9.32 (s, 2H), 7.84 (d, 1H, J = 1.2 Hz), 7.69 (d, 1H, J = 2.4 Hz), 7.67 (s, 1H), 7.38 - 7.19 (m, 8H), 6.67 (d, 1H, J = 8.8 Hz), 6.54 (d, 1H, J = 2.4 Hz), 6.50 (dd, 1H, J = 8.4, 2.4 Hz), 5.84 (d, 1H, J = 9.6 Hz), 4.38 (s, 2H), 4.14 (s, 2H), 3.89 (d, 1H, J = 11.2 Hz), 3.76 - 3.70 (m, 4H), 3.54 (s, 3H), 3.48 (q, 2H, J = 10.8 Hz), 2.29 - 2.26 (m, 1H), 2.03 - 1.94 (m, 2H), 1.80 - 1.70 (m, 1H), 1.60 - 1.58 (m, 2H), 1.26 (t, 2H, J = 5.6 Hz), 0.92 (t, 2H, J = 5.6 Hz).

[0286] Step 6:

[0287] Weigh 10.3 g of the hydrochloride salt of compound E-5 into a reaction flask, add 80 mL of acetonitrile, stir evenly to obtain a suspension solution. Under the condition of room temperature (20 - 25 °C), add an aqueous potassium carbonate solution (4.7 g dissolved in 20 mL of water). The system gradually becomes clear. Directly add 3.8 g of (E)-4-bromo-1-morpholino-2-en-1-one to the reaction system. Then, heat the reaction system to 40 °C and stir overnight. TLC shows that the raw materials are basically completely converted. Let it stand for liquid separation, separate the lower aqueous phase. Concentrate the organic phase under reduced pressure until no liquid drips. Then add dichloromethane and water, combine the previously separated aqueous phase for extraction and liquid separation. Add dichloromethane to the aqueous phase for extraction again. Combine the organic phases and wash with an aqueous sodium chloride solution (20%). Add anhydrous sodium sulfate to the organic phase for drying, filter through silica gel, elute with dichloromethane. Concentrate the filtrate under reduced pressure until 60 mL remains, which is directly used for the next reaction.

[0288] Step 7:

[0289] Transfer the obtained compound E-6 solution to a reaction flask, add 28 g of m-xylene, then add 60 mL of trifluoroacetic acid, heat and stir at 40 °C. After the raw materials are completely converted, directly concentrate the reaction solution until no liquid drips. Add dichloromethane and water to the residue and stir to dissolve. Cool the system to 0 - 10 °C, dropwise add an aqueous sodium carbonate solution (10%) to adjust the pH to 8 - 9. Let it stand for liquid separation. Extract the aqueous phase with dichloromethane again. Combine the organic phases and wash with an aqueous sodium chloride solution (10%). Add anhydrous sodium sulfate to the organic phase for drying. Filter, concentrate the filtrate under reduced pressure until basically no liquid drips. Carry out azeotropic distillation with acetonitrile. Then add acetonitrile to dissolve and stir at room temperature overnight. A large amount of solid precipitates. Filter, wash the filter cake with acetonitrile and filter until no liquid drips. Place the filter cake in a blast drying oven at 50 °C and dry overnight to obtain 3.6 g of the target compound. Concentrate the mother liquor under reduced pressure until basically no liquid drips. After column chromatography, collect the positive fraction and concentrate under reduced pressure until no liquid drips. Add acetonitrile, heat to 50 °C and stir for 2 h. Then turn off the heating, cool to 25 °C and stir overnight. Filter, wash the filter cake with acetonitrile. Place the filter cake in a blast drying oven at 50 °C and dry to obtain 2.9 g of the target compound. Collect compound E-7 (6.5 g, yield: 75%).

Claims

1. A method for preparing a compound of formula V-3 or a pharmaceutically acceptable salt thereof, comprising the steps of reacting a compound of formula V-2 with a compound of formula I-5 under the action of a palladium catalyst, in, R 1 Selected from C 1-6 Alkyl, the C 1-6 The alkyl group is optionally substituted with one or more halogens; R 2 Selected from H or F; R 3 are the same or different, each independently selected from H, halogen or C 1-6 alkyl; m is an integer selected from 0 to 5; R 11 , R 12 The same or different, each independently selected from H or C 1-6 Alkyl, or R 11 and R 12 The carbon atom to which it is attached forms a C 3-8 Cycloalkyl; R 13 , R 14 The same or different, each independently selected from H or C 1-6 Alkyl, or R 13 and R 14 The carbon atom to which it is attached forms a C 3-8 Cycloalkyl; X is selected from Ts or Tf; Y is selected from -B(OR)2, PG is an amino protecting group; R is selected from H or C 1-6 alkyl; Preferably, X is Ts, and Y is Preferably, PG is THP; Preferably, m is selected from an integer of 0-2; Preferably, the palladium catalyst is selected from PdCl2(Xantphos), Pd(OAc)2 or PdCl2(dppf); More preferably, the palladium catalyst is PdCl2(Xantphos).

2. A method for preparing the compound of formula V-3 or a pharmaceutically acceptable salt thereof according to claim 1, the method comprising the step of reacting compound E-2 with compound A-5 to obtain compound E-3, 3. A method for preparing a compound of formula V-2 or a pharmaceutically acceptable salt thereof, comprising the steps of reacting a compound of formula V-1 with an acid anhydride X2O, in, R 1 , R 3 , R 11 , R 12 , R 13 , R 14 , m, and X are as described in claim 1 respectively.

4. The method for preparing the compound of formula V-2 or a pharmaceutically acceptable salt thereof according to claim 3, comprising the step of reacting compound E-1 with p-toluenesulfonic anhydride to obtain compound E-2, 5. The method for preparing the compound of formula V-3 or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 2, further comprising the steps in the method for preparing the compound of formula V-2 or a pharmaceutically acceptable salt thereof according to any one of claims 3 to 4.

6. A method for preparing a compound of formula V-1 or a pharmaceutically acceptable salt thereof, comprising the steps of reacting a compound of formula III-4 with a compound of formula II-3, in, X 1 Selected from F or Cl; R 1 , R 3 , R 11 , R 12 , R 13 , R 14 , m are as described in claim 1 respectively; Preferably, X 1 For Cl.

7. The method for preparing the compound of formula V-1 or a pharmaceutically acceptable salt thereof according to claim 6, comprising the step of reacting compound C-4 with compound B-3 to obtain compound E-1, 8. The method for preparing the compound of formula V-3 or a pharmaceutically acceptable salt thereof according to any one of claims 1-2, further comprising the steps of the method for preparing the compound of formula V-2 or a pharmaceutically acceptable salt thereof according to any one of claims 3-4, and optionally comprising the steps of the method for preparing the compound of formula V-1 or a pharmaceutically acceptable salt thereof according to any one of claims 6-7.

9. A method for preparing a compound of formula V-4 or a pharmaceutically acceptable salt thereof, comprising the step of removing Phth from the compound of formula V-3, in, R 1 , R 2 , R 3 , R 11 , R 12 , R 13 , R 14 , m, and PG are as described in claim 1 respectively.

10. The method for preparing the compound of formula V-4 or a pharmaceutically acceptable salt thereof according to claim 9, comprising the step of removing Phth from compound E-3 to obtain compound E-4, 11. The method for preparing a compound of formula V-4 or a pharmaceutically acceptable salt thereof according to any one of claims 9 to 10, further comprising the steps of the method for preparing a compound of formula V-3 or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 2, optionally comprising the steps of the method for preparing a compound of formula V-2 or a pharmaceutically acceptable salt thereof according to any one of claims 3 to 4, optionally comprising the steps of the method for preparing a compound of formula V-1 or a pharmaceutically acceptable salt thereof according to any one of claims 6 to 7.

12. A method for preparing a compound of formula V-5 or a pharmaceutically acceptable salt thereof, comprising the steps of reacting a compound of formula V-4 with a compound of formula VI, in, R 4 Selected from H, C 1-6 Alkoxy, halogen, C 1-6 alkyl; n is an integer selected from 0 to 5; R 1 , R 2 , R 3 , R 11 , R 12 , R 13 , R 14 , m, PG are as described in claim 1 respectively; Preferably, n is selected from an integer of 0-2; Preferably, R4 is methoxy.

13. The method for preparing the compound of formula V-5 or a pharmaceutically acceptable salt thereof according to claim 12, comprising the step of reacting compound E-4 with 2,4-dimethoxybenzaldehyde to obtain compound E-5, 14. The method for preparing a compound of formula V-5 or a pharmaceutically acceptable salt thereof according to any one of claims 12-13, further comprising the steps in the method for preparing a compound of formula V-4 or a pharmaceutically acceptable salt thereof according to any one of claims 9-10, optionally comprising the steps in the method for preparing a compound of formula V-3 or a pharmaceutically acceptable salt thereof according to any one of claims 1-2, optionally comprising the steps in the method for preparing a compound of formula V-2 or a pharmaceutically acceptable salt thereof according to any one of claims 3-4, optionally comprising the steps in the method for preparing a compound of formula V-1 or a pharmaceutically acceptable salt thereof according to any one of claims 6-7.

15. A method for preparing a compound of formula V-6 or a pharmaceutically acceptable salt thereof, comprising the steps of reacting a compound of formula V-5 with a compound of formula VII, in, R 5 and R 6 are the same or different, independently selected from H, C 1-6 Alkyl, or R 5 and R 6 The nitrogen atom to which it is attached forms a 4-6 membered heterocyclic ring, wherein the 4-6 membered heterocyclic ring optionally contains an oxygen atom; R 1 , R 2 , R 3 , R 11 , R 12 , R 13 , R 14 , m, PG are as described in claim 1 respectively; L is selected from halogen; R 4 , n are as described in claim 12 respectively.

16. The method for preparing the compound of formula V-6 or a pharmaceutically acceptable salt thereof according to claim 15, comprising the step of reacting compound E-5 with compound F to obtain compound E-6, 17. A method for preparing a compound of formula V-6 or a pharmaceutically acceptable salt thereof according to any one of claims 15-16, further comprising the steps of a method for preparing a compound of formula V-5 or a pharmaceutically acceptable salt thereof according to any one of claims 12-13, optionally comprising the steps of a method for preparing a compound of formula V-4 or a pharmaceutically acceptable salt thereof according to any one of claims 9-10, optionally comprising the steps of a method for preparing a compound of formula V-3 or a pharmaceutically acceptable salt thereof according to any one of claims 1-2, optionally comprising the steps of a method for preparing a compound of formula V-2 or a pharmaceutically acceptable salt thereof according to any one of claims 3-4, optionally comprising the steps of a method for preparing a compound of formula V-1 or a pharmaceutically acceptable salt thereof according to any one of claims 6-7.

18. A method for preparing a compound of formula V-7 or a pharmaceutically acceptable salt thereof, comprising removing PG from a compound of formula V-6 and Steps, in, R 1 , R 2 , R 3 , R 11 , R 12 , R 13 , R 14 , m, PG are as described in claim 1 respectively; R 4 , n are respectively as described in claim 12; R 5 , R 6 As described in claim 15 respectively.

19. The method for preparing the compound of formula V-7 or a pharmaceutically acceptable salt thereof according to claim 18, comprising the step of removing THP and DMB from compound E-6 to obtain compound E-7, 20. The method for preparing a compound of formula V-7 or a pharmaceutically acceptable salt thereof according to any one of claims 18 to 19, further comprising the steps of the method for preparing a compound of formula V-6 or a pharmaceutically acceptable salt thereof according to any one of claims 15 to 16, optionally comprising the steps of the method for preparing a compound of formula V-5 or a pharmaceutically acceptable salt thereof according to any one of claims 12 to 13, optionally comprising the steps of the method for preparing a compound of formula V-4 or a pharmaceutically acceptable salt thereof according to any one of claims 9 to 10, optionally comprising the steps of the method for preparing a compound of formula V-3 or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 2, optionally comprising the steps of the method for preparing a compound of formula V-2 or a pharmaceutically acceptable salt thereof according to any one of claims 3 to 4, and optionally comprising the steps of the method for preparing a compound of formula V-1 or a pharmaceutically acceptable salt thereof according to any one of claims 6 to 7.

21. A compound C-4 or a pharmaceutically acceptable salt thereof, 22. A compound represented by formula V-1 or a pharmaceutically acceptable salt thereof, in, R 1 , R 3 , R 11 , R 12 , R 13 , R 14 , m are as described in claim 1 respectively.

23. The compound represented by formula V-1 according to claim 22 or a pharmaceutically acceptable salt thereof, which is compound E-1 24. A compound represented by formula V-2 or a pharmaceutically acceptable salt thereof, in, R 1 , R 3 , R 11 , R 12 , R 13 , R 14 , m, and X are as described in claim 1 respectively.

25. The compound represented by formula V-2 according to claim 24 or a pharmaceutically acceptable salt thereof, which is compound E-2 26. A compound represented by formula V-3 or a pharmaceutically acceptable salt thereof, in, R 1 , R 2 , R 3 , R 11 , R 12 , R 13 , R 14 , m, and PG are as described in claim 1 respectively.

27. The compound represented by formula V-3 or a pharmaceutically acceptable salt thereof according to claim 26, which is compound E-3 28. A compound represented by formula V-5 or a pharmaceutically acceptable salt thereof, in, R 1 , R 2 , R 3 , R 11 , R 12 , R 13 , R 14 , m, PG are as described in claim 1 respectively; R 4 , n are as described in claim 12 respectively.

29. The compound represented by formula V-5 or a pharmaceutically acceptable salt thereof according to claim 28, which is compound E-5, 30. A compound represented by formula V-6 or a pharmaceutically acceptable salt thereof, in, R 1 , R 2 , R 3 , R 11 , R 12 , R 13 , R 14 , m, PG are as described in claim 1 respectively; R 4 , n are respectively as described in claim 12; R 5 , R 6 As described in claim 15 respectively.

31. The compound represented by formula V-6 according to claim 30 or a pharmaceutically acceptable salt thereof, which is compound E-6

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